This invention relates to implant materials having access channels for enhanced cell-mediated resorption of the implant into living tissue. This invention also relates to materials for the cell-mediated remodeling of an implant.
Damage to body tissue often requires the use of an implant material to replace, support or repair the damaged tissue. For example, implants may be used in the repair of bone fractures or periodontal defects, replacement of damaged cartilage and soft tissues such as muscle tissue and collagen.
In the case of fracture, disease or other injury to bone, proper healing and bone remodeling depends on the successful stabilization of the bone site and the ability to induce bone regeneration and repair. In the instances where damage to the bone is large, a bone graft material (implant) may be introduced into the bone site to bridge the gap left by the damaged bone in order to fill open spaces and prevent fibrous ingrowth into the defect, as well as to aid in the stabilization of the fracture. Often times a resorbable bone graft material is selected to serve this function. Both biologically derived materials such as autographs and allografts, as well as synthetic glasses, calcium phosphates and calcium sulfates, are examples of resorbable bone graft materials.
A variety of synthetic bone implants have been shown to be resorbed or partially resorbed by host cells. Cells which are recognized as important in the resorption process include osteoclasts, osteoblasts, macrophages and vascularizing elements. Since these cells necessarily gain access to the implant by way of the surface, specific surface characteristics may significantly affect remodeling and resorption rates. For example, the ratio of implant surface area to implant volume is expected to have significant ramifications on implant resorption and remodeling rates by cells.
A variety of materials have been proposed for use as bone implant materials, including porous metals, biodegradable organic polymers, and ceramic materials. The use of calcium phosphate materials as implants in bone sites is known. Calcium phosphate cements represent biocompatible materials which provide the components necessary for the formation of bone, namely, calcium and phosphate ions, and which may act as a substrate for bone growth, i.e., they are osteoconductive.
Materials for use as implants range from substantially non-resorbable materials, i.e., porous metals, bioglass and corraline, to highly resorbable materials, i.e., selected organic polymers, calcium phosphates, and composites thereof. In most applications, it is desirable to have materials which are highly resorbable, and which can be replaced by living tissue in a short time period. Furthermore, the implant material ideally is capable of being formed into complex shapes that fit the contours of the repair site. An accurately contoured implant will enhance the integration of natural tissue at the site.
Calcium phosphate cements are known, which set rapidly at room and/or body temperature. See, U.S. Pat. Nos. 5,522,893, 5,525,148, RE 33,161 and RE 33,221 to Chow et al, U.S. Pat. No. 5,605,713 to Boltong et al. and U.S. Pat. No. 5,336,264 to Constantz et al. Such cements provide the ability to form complex shapes with intimate host bone contact, however, the osteoconductivity and the remodeling capability of the resulting material may often be less than desired.
Lee et al. in U.S. Pat. Nos. 5,683,461 and 5,783,217 describe a bioresorbable calcium phosphate cement which is an excellent osteoconductive substrate. The calcium phosphate implant is resorbed in as little as 3-12 weeks in small animal models, and bone tissue substantially similar to naturally occurring bone is formed in its place. Even in these calcium phosphate cements, the remodeling capability sometimes is less than ideal, particularly when they are used to produce large volume implants.
Porosigens have been used to increase porosity in materials. Porosigens include additives, usually particulate in nature, which are leached out or dissolved to form pores or voids which increase the porosity of the implant. While porosigens have been associated with increased resorbability, known porosigens do not provide adequate access to the interior of the implant on a scale sufficient to permit cell-mediated resorption or remodeling of the implant.
Chow et al in U.S. Pat. No. 5,525,148 report the use of pore-forming agents to create pores sufficiently large to cause vascularization of tissue which infiltrates the cement once placed in the body. Chow reports the addition of particulate additives such as sugars, sodium bicarbonate or phosphate salts, which are removed by resorption into the body tissue, dissolution in physiological fluids, or heating after the cement has hardened (presumably before implantation). Due to the nature of the particulate additive, the pores are on the micron or submicron scale, i.e., xe2x80x9cnon-macroxe2x80x9d scale, and the internal porosity remaining after the porosigen is removed is random and often non-continuous.
Solid ceramic implants have been prepared in a variety of sizes and shapes.
Johnson et al. in WO 99/16479, entitled xe2x80x9cBone Substitute Materialsxe2x80x9d, describe a hard, open ceramic framework as a bone implant material. The porous structure is obtained by coating an open-celled organic material with a ceramic oxide and then sintering to burn out the open-celled material.
Boyan et al. in U.S. Pat. No. 5,492,687, entitled xe2x80x9cBiodegradable Implant for Fracture Nonunions,xe2x80x9d describe a substitute bone graft material having interconnected pores and canals having the size, shape and spacing corresponding to Haversian canals, i.e., naturally occurring canals of cortical bone which allow vascularization. The implant is formed by casting a polymeric gel into the desired shape, including channels, and drying to form a solid implant.
In the above examples, the implant is a solid structure in which the porous substructure is introduced into the material prior to implant. Such implant structures are not moldable or able to form complex shapes with intimate host bone contact.
There remains a need to provide an implant material and methodology, in which access into the interior of the implant material is provided, while retaining the host-conforming ability of a paste or putty.
Furthermore, there remains a need to increase the rate and level of cellular ingress into the implant so that the remodeling rate and efficiency of implant material is enhanced.
There remains a need for providing greater access to cells of living tissue to the interior of an implant material to increase implant resorption and tissue remodeling.
The present invention provides means for cellular access into the interior of a malleable implant to optimize cell contact with the implant material. The access means is a macrostructure that provides access to the interior of a soft, conformable implant material, which upon hardening provides a structural access channel for cells to the interior of the implant.
In one aspect, the inventive implant includes a malleable implant material, and a non-particulate access means for providing macroscopic access into the interior of the implant to cells of the living tissue.
In preferred embodiments, the implant has at least one cross-sectional dimension of greater than 3 mm, and preferably at least one cross-sectional dimension of greater than 1 cm.
In other preferred embodiments, the malleable implant material is comprised of a bioresorbable material and a physiologically acceptable fluid. The malleable material is selected from the group consisting of calcium phosphates, collagens, and fibrins. In one embodiment, the malleable implant material is hardenable, or the malleable implant material is an osteoconductive material.
In one embodiment, the calcium phosphate is selected from the group consisting of amorphous calcium phosphate, tricalcium phosphate, hydroxyapatite, calcium deficient hydroxyapatite, poorly crystalline hydroxyapatite (PCHA), calcium deficient hydroxyapatite, dicalcium phosphate dihydrate (DCPD), tetracalcium phosphate, and dablite (Ca5(PO4,CO3)3F).
In a preferred embodiment, the non-particulate access means is selected from the group consisting of tubes, rods, fibers, sheets, star-shapes, jack-shapes, fibrous mats, and complex structures. The non-particulate access means may be hollow and open at at least one end and contactable with living tissue, and having an inner diameter of a size which permits access by cells of the living tissue. The non-particulate access means may be solid, having at least one end contactable with living tissue, and having an outer diameter of a size which permits access by cells of the living tissue. In one embodiment, the non-particulate access means is non-resorbable, and may be selected from the group consisting of sintered ceramics, poly(methylmethacrylate), and high molecular weight polyethylene. In other embodiments, the non-resorbable non-particulate access means is positioned and arranged so that the macrostructure terminates in the interior of the implant.
In one embodiment, the non-particulate access means is resorbable, and may be selected from the group consisting of poly(lactide), poly(lactide-co-glycolide), gelatins, collagen, alginate, tissue culture medium, calcium phosphates, calcium sulfate, sugars, carbohydrates, and salts. The non-particulate access means includes a material resorbable by dissolution, enzymatic or cellular action to provide cellular access to the interior of the implant, and preferably includes a nutrient of a cell of the living tissue.
In other embodiments, the non-particulate access means includes a polymer capable of acting as a substrate for cell attachment, and further may include a material for promoting cell adhesion.
In preferred embodiments, the non-particulate access means has a dimension greater than 0.5 mm, and preferably a dimension greater than 1 mm, and more preferably greater than 5.0 mm.
In other preferred embodiments, the non-particulate access means is insertable into the malleable implant material at an implant site. In one embodiment, the implant is a multilaminar structure having layers of malleable implant material and non-particulate access means. In other embodiments, the non-particulate access means is heterogeneously distributed throughout the implant.
In other preferred embodiments, the non-particulate access means includes a mechanically weak material susceptible to fracture at an implant site thereby resulting in channels or cracks, and may be selected from the group consisting of hydrogels, oils, lipids, lubricants, sugars and salts.
In one embodiment, the inventive implant further includes additives capable of controlling the resorption rate of the implant material, and may be selected from the group consisting of bone morphogenic protein, OP-1 parathyroid hormone, parathyroid-hormone-related peptide, 1,25-dihydroxyvitamin D, interleukin-1, tumor necrosis factor, thyroid hormones, vitamin A, transforming growth factor/epidermal growth factor, fibroblast growth factor, heparin, bacterial endotoxin, thrombin, bradykinin, prostaglandin E2 and other protanoids, transforming growth factor xcex2, lymphocyte inhibitory factor/differentiation inducing factor, calcitonin and related peptides, interferon-xcex3, glucocortinoids, estrogens and androgens.
In another embodiment, the inventive implant further includes reinforcing additives.
In another aspect of the invention, a kit is provided having a powder for use in preparing a paste, and a macrostructure insertable into a paste, said macrostructure providing access to a cell to the interior of the paste. In preferred embodiments, the powder includes a calcium phosphate. In other preferred embodiments, the kit further includes a mixing pouch, or a physiologically acceptable fluid.
In yet another aspect of the invention, a method of enhancing remodeling at an implant site is provided. The method includes the steps of implanting a malleable implant material at a host site and, before or after the step of implantation, introducing non-particulate access means into the malleable implant material for providing macroscopic access into the interior of the implant material to cells of the host, whereby cells of the host are introduced into the interior of the implant material. In preferred embodiments, the access means are introduced after implantation.
In one embodiment, host cells preferentially act upon the access means to degrade and thereby remove the access means to create a conduit within the implant.
In preferred embodiments, the method includes an implant having at least one cross-sectional dimension of greater than 3 mm, and preferably at least one cross-sectional dimension of greater than 1 cm.
In other preferred embodiments, the method includes a malleable implant material comprised of a bioresorbable material and a physiologically acceptable fluid, and the malleable implant material may be hardenable or it may be an osteoconductive material, such as calcium phosphates, collagens, and fibrins.
In other embodiments, the calcium phosphate is selected from the group consisting of amorphous calcium phosphate, tricalcium phosphate, hydroxyapatite, calcium deficient hydroxyapatite, poorly crystalline hydroxyapatite (PCHA), calcium deficient hydroxyapatite, dicalcium phosphate dihydrate (DCPD), tetracalcium phosphate, and dahlite (Ca5(PO4,CO3)3F).
In yet other embodiments, the method includes non-particulate access means selected from the group consisting of tubes, rods, fibers, sheets, star-shapes, jack-shapes, fibrous mats, and complex structures. It may be hollow and open at at least one end, contactable with living tissue, and having an inner diameter of a size which permits access by cells of the living tissue. It may be solid, having at least one end contactable with living tissue, and having an outer diameter of a size which permits access by cells of the living tissue.
In some embodiments, the method includes non-resorbable, non-particulate access means is non-resorbable, and may be positioned and arranged so that the macrostructure terminates in the interior of the implant.
In other embodiments the method includes resorbable, non-particulate access means and may be selected from the group consisting of poly(lactide), poly(lactide-co-glycolide), gelatins, collagen, alginate, tissue culture medium, calcium phosphates, calcium sulfate, sugars, carbohydrates, and salts. The non-particulate access means is comprised of a material resorbable by dissolution, enzymatic or cellular action to provide access to the interior of the implant. The non-particulate access means is comprised of a nutrient of a cell of the living tissue, or a polymer capable of acting as a substrate for cell attachment. The implant may further include a material for promoting cell adhesion.
In yet other embodiments, the method includes a non-particulate access means having a dimension greater than 0.5 mm, preferably greater than 1 mm, and more preferably greater than 5.0 mm.
In other embodiments, the non-particulate access means is inserted into the malleable implant material at an implant site, or it may be a multilaminar structure having layers of malleable implant material and non-particulate access means, or it may be heterogeneously distributed throughout the implant.
In other embodiments, the method includes a mechanically weak non-particulate access means susceptible to fracture at an implant site and a force is applied to the implant to thereby result in channels or cracks.
In still other embodiments, the implant may further include additives capable of controlling the resorption rate of the implant material, or reinforcing additives.
xe2x80x9cAccess meansxe2x80x9d is used herein to mean a structural element that is introduced into an implant material to provide cells access to the implant interior. The access means may provide such access either by providing empty conducts, voids or channels through which cells may pass, or by preferential resorbability or dissolution, or by preferential material failure which has the effect of introducing breaks, channels or other access pathways into the implant interior.
xe2x80x9cBiocompatiblexe2x80x9d means that the material does not elicit a substantial detrimental response in the host, such as for example, an immune response or an inflammatory response having a negative effect on the host. A material is considered biocompatible when the host responses are within medically acceptable ranges.
xe2x80x9cBioresorbablexe2x80x9d means the ability of a material to be resorbed or remodeled in vivo. The resorption process involves degradation and elimination of the original implant material through the action of body fluids, enzymes or cells. The resorbed materials may be used by the host in the formation of new tissue, or it may be otherwise re-utilized by the host, or it may be excreted.
xe2x80x9cCellular action or processxe2x80x9d involves an enzymatic or metabolic process carried out by a cell. The degradation and/or breakdown of the implant material resulting from the cellular process may be the result of enzymatic processes involving enzymes such as phosphatase which hydrolyzes phosphomonoesters (phosphates) or hydrolase which catalyzes the hydrolysis of a variety of bonds, such as esters, glycosides, peptides or by means of cell-mediated acidification as is known to occur during osteoclast resorption of bone.
xe2x80x9cImplant interiorxe2x80x9d is that portion of the implant which is not immediately accessible from the surface, or which is accessible to the surface only through an access channel and is some distance from the surface. Generally, as used herein implant interior refers to a portion of the implant which is, at the time of implantation, more than 5 mm from any surface, more than 2 mm and always 1 mm from the implant outer surface. Determination of distance from surfaces is not measured from any surface defining an access channel.
xe2x80x9cMacrostructurexe2x80x9d means a structure having dimensions on the order of millimeters or more. The macrostructure preferably has at least one cross-sectional dimension of at least 0.1 mm, and more preferably at least 1.0 mm. The dimension of the structure is selected to accommodate cells, blood vessels (vasculature) and other organelles needed to sustain the living tissue. Osteoclasts, which are a preferred cell for remodeling of bone, typically have diameters on the order of 0.1-0.3 millimeters. Vascularization generally requires even larger access dimensions to accommodate the multitude of capillaries formed in the vascularization process.
xe2x80x9cMalleablexe2x80x9d means capable of being shaped or deformed under pressure or other force. In the present invention, the pressure is applied in conjunction with introduction or insertion of channel makers into the malleable implant paste, or introduction of the malleable implant material into an implant site.
xe2x80x9cNon-particulatexe2x80x9d means a material that is not in a powder or a particulate form, that is, the material is not a powder, fragment, granule, grain or particle. However, the material may be comprised of particulate subcomponents which have been combined to form a larger unitary structure, such as can be obtained using powder compaction and powder pressing techniques. The non-particulate member has at least one cross-sectional dimension on the order of at least 0.1 mm, preferably at least 1 mm and more preferably at least 0.5 cm, and can range much higher, e.g. xcx9c5 cm, in some instances.
xe2x80x9cResorptionxe2x80x9d means the loss of substance (mass) through physiological means, such as those processes involved in loss of dentin and cementum of a tooth or of the alveolar process of the mandible or maxilla. In the present invention, resorption involves the loss of implant mass which has been introduced into the host body through normal physical (e.g., dissolution) or physiological processes. xe2x80x9cCellularly resorbablexe2x80x9d means a that a material is resorbable by a process involving a cellular process.
xe2x80x9cRemodelingxe2x80x9d is related to resorption and is the process of coordinately replacing or transforming the resorbed material into tissue without the formation of significant unwanted voids or detrimental intermediates. An exemplary remodeling is the coordinated resorption of a calcium phosphate bone cement and its replacement with new bone.